PT Unknown AU Lange, C TI Molecular analysis of the innate immune response in hydra PY 2010 PU Christian-Albrechts-Universität zu Kiel WP https://macau.uni-kiel.de/receive/diss_mods_00005554 LA en DE Hydra; NOD-like receptors; innate immunity; pattern recognition; NOD-artige Rezeptoren; angeborene Immunität; Mustererkennung AB The initial sensing of invading potential pathogenic microorganisms by pattern recognition receptors (PRRs) of the innate immune system is pivotal for the survival of the host. Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) are a family of cytoplasmic PRRs that recognize conserved microbe-associated molecular patterns (MAMPs) or endogenous danger signals. Upon activation, these proteins trigger the release of pro-inflammatory cytokines and antimicrobial peptides (AMPs) via a variety of signal transduction cascades in mammals. All pathways have in common the initial formation of a multimeric complex of the activated NLR and downstream signalling proteins through homophilic interactions of effector domains. Many genetic variants of NLRs have been linked to chronic inflammatory disorders of the human epithelial barrier organs. Although these receptors are of fundamental importance for understanding the maintenance of the human barrier integrity not much is known about their evolutionary roots. This thesis involved screening the genomes of a variety of animal species with a focus on basal Metazoa and particularly on the freshwater polyp Hydra for NLR orthologues. It was subsequently demonstrated that the family of NLRs is evolutionary conserved and that frequently throughout animal evolution species-specific gene-amplifications occurred. Hydra is continually surrounded by potential pathogenic microorganisms and must rely on an effective epithelial defence machinery. Using Hydra as a model organism for epithelial defence, the expression profile of one of the identified Hydra NLRs, HyNLR type 1 was analysed in detail. This gene is predominantly expressed in the endodermal epithelium and is subject of alternative splicing. A co-expressed putative HyNLR-interactome has been identified as well. First functional in vitro studies using an artificially activatable chimeric protein including the N-terminal part of HyNLR type 1 could show that Hydra caspases may link NLR signalling to apoptosis as an ancient mechanism of innate immune defence. As well as a genetic background, environmental changes and an altered composition of the host’s microbiota are proposed to contribute to the development of barrier diseases. A tumour bearing Hydra strain with an altered microbial composition was analysed using histological and molecular biological techniques. The tumour was shown to be composed of female germline-determined interstitial stem cells. The tumour-like structure shows numerous parallels to oogenesis in Hydra, including lipid storage, the appearance of nurse cells and the expression of germline-specific genes. This first detailed description of tumour formation in a basal eumetazoan animal provides new possibilities for the analysis of an imbalanced tissue homeostasis. PI Kiel ER